An allergy refers to a phenomenon that an organism develops an excessive immune response to a specific allergenic agent, namely, an antigen designated as an allergen. A variety of foreign substances derived from the environment to which an organism is exposed under its living environment can become an allergen (an allergenic agent) that causes an allergy. Typical allergic diseases induced by various foreign substances, such as pollen, foods, body compositions or dejections of animals, molds, chemicals and drugs, include allergic rhinitis (pollen allergies), allergic conjunctivitis, food allergies, and drug allergies.
These allergic diseases develop when any of the aforementioned allergenic agents, which works as an allergen by itself or does not work as an antigen by itself but is changed to an allergen by binding to a macromolecule such as a protein in the body, elicits an excessive immune response causing an allergy.
Conditions caused by allergies, particularly by drug allergies, include relatively mild drug rashes and blood disorders, severe drug rashes known as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS), as well as serious conditions causing sequela or death at the worst, such as organ dysfunction of, for example, liver, lung or digestive tube, and anaphylactic shock.
Drug withdrawal due to the development of a drug allergy, which means interruption of the treatment of the primary disease, should be avoided by preventing the allergy.
However, means for preventing allergic diseases are limited. Response to a drug is greatly different among individuals and may be influenced by multiple factors including concomitant drugs. Among currently performed allergy tests, an intradermal test or patch test performed in advance to administering a drug cannot always accurately predict development of an allergy to the drug. A drug challenge test is undesirable because it imposes a large burden on the patient and increases risk of shock if an allergy is induced.
Accordingly, once a drug allergy develops, careful and rapid detection and determination of the causative agent is desired.
The causative agent for a drug allergy is currently detected or determined by, for example, a drug-induced lymphocyte stimulation test (DLST) or a leukocyte migration test (LMT). In addition, a time-consuming drug elimination method in which a suspected drug is withdrawn may be employed.
The DLST and the LMT are useful, in view of safety, because blood collected from the patient is tested. The patient is not involved after the blood collection. Disadvantages of the tests include that the tests need approximately 10 ml of blood for each drug to be tested, require about one week for obtaining the result and could give false positive reactions.
A drug allergy can be caused by any of allergic mechanisms including types I to IV. For planning treatment and relief of a symptom presented by a patient, it is important to establish a definitive diagnosis that the symptom is a drug allergy through an immune response or the symptom is a non-allergic adverse reaction (pseudo reaction) involving no immune response.
In a blood test for diagnosing an allergy, indicators such as eosinophils and IgEs are generally measured. Though many of such indicators can be used or referred to for diagnosing an allergic state for example in type I allergy, they are not universal indicators and cannot be used for the definite diagnosis of all types of allergies.
In addition, positive rates are not very high in tests such as the DLST (Non Patent Literatures 1 and 2). One of the reasons is probably that it fails to exclude pseudo reactions different from drug allergies.
On the other hand, it has been revealed that a specific human histocompatibility antigen (HLA) genotype is a risk factor of severe SJS or TEN developed after taking allopurinol, a gout suppressant, or carbamazepine, an antiepileptic drug in south Asians, particularly Chinese people (Non Patent Literatures 3 and 4). Methods for predicting a risk of a drug based on the HLA gene has been developed (Non Patent Literature 5). However, this method is used only for avoiding the risk and is not sufficient.
Accordingly, there is a demand for a method which can test a drug allergy accurately, and a method which can efficiently and sensitively test or determine a drug that could induce a drug allergy, for the purpose of selecting an alternative drug for treating the primary disease in a patient.